The cold menthol receptor TRPM8 (also referred to as Cold Membrane Receptor (CMR)1) belongs to the family of the “Transient Receptor Potential Ion Channels”, is specifically expressed in a special group of neurons and, in the cell membrane, forms pores (in each case 4 units combine to give a tetramer), which selectively allow Ca2+ ions to pass. The protein has 6 transmembrane domains and a cytoplasmatic C and N terminus. Low temperatures (preferably 10-25° C.) stimulate this receptor, resulting in a signal transduction which is interpreted by the nervous system as a sensation of coldness. The receptor was described for the first time in 2002 as cold receptor in a number of publications (Peier A M et al., A TRP channel that senses cold stimuli and menthol. Cell. 2002 Mar. 8; 108(5):705-15; McKemy D D et al. Identification of a cold receptor reveals a general role for TRP channels in thermosensation Nature 2002 Mar. 7; 416 (6876): 52-8; Zuker C S. Neurobiology: A cool ion channel Nature 2002 Mar. 7; 416 (6876): 27-8).
Cooling compounds, such as e.g. menthol, have for a long time played an important role in the flavorings and fragrance industry in order to produce an association with freshness and cleanliness. For the compound menthol, it has been shown that it acts as a natural modulator of the receptor TRPM8 (McKemy D. D., Molecular Pain 1, 2005, 16; McKemy D. D., Nature 416, 2002, 52-58; Peier A. M., Cell 108, 2002, 705-715; Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161). By applying menthol, TRPM8 is activated, which brings about a Ca2+ influx into the cold-sensitive neurons. The electrical signal produced as a result is ultimately perceived as a sensation of coldness. Elevated menthol concentrations lead to irritation and an anesthetic effect. Moreover, various publications have described menthol derivatives with a similar effect (British Patent 1971 #1315761 Watson H. R., J. Soc. Cosmet. Chem. 29, 1978, 185-200; Furrer S. M., Chem. Percept. 1, 2008, 119-126). There are also individual compounds, structurally unrelated to menthol, which bring about a significant TRPM8 modulation, such as e.g. Icilin (Wei E. T., J. Pharm. Pharmacol. 35, 1983, 110-112; WO 2004/026840), WS-23 or compounds listed in the patent application WO 2007/019719.
Further effects of substances which modulate the TRPM8 receptor and/or its insect analogs are a repellent effect on insects (WO 2002/015692; WO 2004/000023, US 2004/0028714), and also activity in antitumor therapy (e.g. an influencing of prostate tumors), activity in the treatment of inflammatory pain/hyperalgesia and an effect as TRPM8 antagonists in the treatment of bladder syndrome or overactive bladder (Beck B. Cell Calcium, 41, 2007, 285-294; Levine J. D. Biochim. Biophys. Acta, Mol. Basis Dis. 1772, 2007, 989-1003; Mukerji G., BMC Urology 6, 2006, 6; US 2003/0207904; US 2005/6893626, Dissertation Behrendt H. J. 2004, Universität Bochum; Lashinger E. S. R. Am. J. Physiol. Renal Physiol. Am J Physiol Renal Physiol. 2008 Jun. 18. [Epub ahead of print]; PMID: 18562636).
However, many of the TRPM8 modulators found hitherto have deficiencies with regard to strength of effect, duration of effect, skin/mucosa irritation, odor, taste, solubility and/or volatility.
The international patent application WO 2010/026094 by the applicant proposes individual specific compounds for modulating the TRPM8 receptor. These comprise the following specifically disclosed compounds:
where the compound may be present in chemically pure or enriched form, as individual stereoisomer or in the form of stereoisomer mixtures.
Moreover, WO 2011/061330 from the applicant describes three new types of substance classes of generic TRPM-8 modulators.
There continues to be a need for further substances for modulating the TRPM8 receptor; in particular substances for inducing a sensation of coldness on skin and mucosa.